ABSTRACT Focal and Segmental Glomerulosclerosis (FSGS), Minimal Change Disease (MCD) and Membranous Nephropathy (MN), presenting as Nephrotic Syndrome (NS), are rare diseases causing catastrophic complications and end stage kidney disease, generating enormous individual, societal and economic burdens. The clinical, histopathology-based taxonomy of NS is inadequate and fails to capture the molecular bases of these diseases and does not adequately predict their natural history or response to therapy. A Precision Medicine (PM) approach is necessary to define NS in molecular terms, to identify therapeutic targets and match patients to treatments. NEPTUNE was applied an innovative, investigational strategy to improve the diagnosis, management and treatment of NS. In the first two project periods, a translational and clinical research infrastructure has been established, participants enrolled, biosamples collected, key collaborations forged and an outreach strategy deployed. NEPTUNE has established a robust investigative infrastructure encompassing 26 academic centers and two patient interest groups, has recruited more than 750 rigorously phenotyped NS participants with detailed clinical, histological, genetic, transcriptomic and proteomic data sets. This comprehensive information has been integrated in the NEPTUNE Knowledge Network for easy access by the NS research community. With substantial support from the patient interest group NephCure Kidney International, NEPTUNE has established robust training and ancillary study programs with 112 ancillary studies ranging from methods development to successful Phase II clinical trials. These critical advances have resulted in a significant interest in NS clinical trials, with more than 15 trials now in the advanced planning or enrollment phase. In this renewal application, we propose to leverage the NEPTUNE resources to catalyze discovery, training and outreach as we strive to improve health outcomes for individuals affected by NS. The overarching goal is to apply a PM approach to NS, leveraging the extensive NEPTUNE Knowledge Network established over the past 9 years. NEPTUNE will implement this PM strategy to permit discovery of novel therapeutic targets and deploy the patient stratification approach developed in the current funding cycle to help identify the right trial for the right patient at the right time: Patient stratification approaches will be utilized for targeted enrollment into clinical trials. Patients will undergo intense profiling at the time of disease presentation or at follow-up renal biopsy in order to match the disease mechanism active with ongoing clinical trials in a precompetitive, public private partnership with leading companies in the field. Training, pilot and ancillary study programs will continue with significant funding support from NKI. NEPTUNE will maintain its engagement with lay communities, clinicians, scientists, regulatory agencies and the pharmaceutical industry to identify and move therapeutic targets to our patients through an effective translational research pipeline for NS.